Pharmacokinetic models of antifolate therapy with citrovorum rescue will be developed from laboratory data obtained on patients undergoing high-dose MTX treatments. Citrovorum kinetics will be added to the multicompartment flow model of Bischoff-Dedrick-Zaharko. It will be ascertained if MTX and CF urinary clearances, MTX, CF, DHFR, and folate tissue distributions (especially marrow and tumor) and MTX facial clearances provide the necessary input to allow accurate pharmacokinetic simulations of the time course of intracellular MTX and CF concentrations. Efforts will be made to correlate free intracellular MTX and CF concentrations with toxicity measures including inhibition of deoxyuridine incorporation and bone-marrow depression. The pharmacokinetic model will also be expanded to include a compartment representing the CSF space. The ability of simple single tissue pharmacokinetic models to simulate drug histories after characteristic drug loading times will also be investigated. This should allow experimentally-measured drug plasma levels to be used directly to determine target cell intracellular concentrations. This should lead to improved treatment plans tailored to the individual patient.